1. Field of the Invention
This invention pertains to novel medicated compositions useful in treating ulcers. More particularly, this invention pertains to novel chewable spray dried spheroidal microcapsules and taste masking compositions. The novel microcapsule compositions comprise sucralfate and a polymer soluble in the gastric fluids. In one embodiment, therapeutically effective amounts of the sucralfate microcapsules may be incorporated into a matrix comprising a bulking agent and a lubricating agent and compressed into tablets to prepare taste masking compositions. In another embodiment, therapeutically effective amounts of the sucralfate microcapsules may be utilized in a wide variety of pharmaceutically acceptable carriers and confectionery bulking agents to prepare medicated products having taste masking properties. This invention also relates to methods for preparing these chewable spray dried spheroidal microcapsules and the medicated taste masking compositions in which they may be used.
2. Description of the Prior Art
Peptic ulcers are lesions in the mucous membrane of the esophagus, stomach or duodenum caused by gastric acid and pepsin. Peptic ulcers are believed to be caused by hypersecretion of gastric fluids or decreased resistance of the mucous membrane to the action of gastric acids and pepsin.
The methods for treating ulcers include diet modification, surgical removal of the ulcer, and the use of drugs. Useful antiulcer drugs include antacids, which neutralize excess acid secretion; anticholinergics, which diminish acid secretion; histamine H.sub.2 receptor blocking agents, which block gastric acid secretion; prostaglandins, which increase mucous membrane resistance to gastric fluids; prokinetic agents, which enhance gastrointestinal motility; and gel forming compositions, which form ulcer protective barriers.
A gel forming drug in this last category is sucralfate, which is well known in the art as a basic aluminum sucrose sulfate complex which accelerates the healing of peptic ulcers. The mechanism by which sucralfate works is not fully understood but it is known that the sulfated disaccharide is not absorbed from the gastrointestinal tract and that the antiulcer activity is therefore exerted locally and not systemically. Sucralfate has a greater affinity for ulcerated mucosa than for non-ulcerated mucosa and produces morphological and functional changes in the mucosa. These changes include mucus release, changes in ion transport and increased release and synthesis of prostaglandins (i.e., prostaglandin E.sub.2) from the mucosa.
At pH values below about 3.5, sucralfate coagulates to form a gel-like mass. In the gastrointestinal tract, this gel-like mass concentrates at ulcer sites to produce an ulcer adherent cytoprotective barrier with proteinaceous exudate. This protein barrier (a) binds to the ulcer site to form a protective barrier which blocks diffusion of hydrogen ions, (b) adsorbs bile salts and inhibits the potential ulcerogenic properties of pepsin, and (c) blocks back diffusion of gastric acid across the sucralfate protein barrier. The antiulcer effects of sucralfate are not attributed to neutralization of gastric acid because sucralfate has negligible acid-neutralizing capability.
The relatively large dosage level of sucralfate of one (1) gram four times daily presents certain drawbacks in administering sucralfate antiulcer therapy. Non-chewable tablets or capsules are physically very large and may be objectionable to certain consumers. Hard chewable tablets offer the ability to deliver large dosages of sucralfate, however, the resulting products have a gritty mouth feel and are dominated by the astringent taste of sucralfate.
U.S. Pat. No. 4,772,470, issued to Inoue et al. and assigned to Nitto Electric Industrial Co., Ltd., discloses an oral bandage comprising a film support for a soft adhesive film comprised of a mixture of a polycarboxylic acid and/or a polycarboxylic acid anhydride and a vinyl acetate polymer. The oral bandage may have incorporated therein a topical drug such as sucralfate for administration to the oral mucosa.
U.S. Pat. No. 4,704,278, issued to Wu et al. and assigned to American Home Products Corp., discloses an aqueous antacid composition of fluidized magaldrate suspension comprising magaldrate gel (aluminum hydroxide and magnesium hydroxide) and a fluidizing amount of a combination of an aluminum hydroxide gel as a first fluidizer and a pharmaceutically acceptable citric ion source as a second fluidizer. The composition may also contain other therapeutically active substances such as sucralfate.
U.S. Pat. No. 4,676,984, also issued to Wu et al. and assigned to American Home Products Corp., discloses an aqueous antacid composition of fluidized magaldrate suspension comprising magaldrate gel and a fluidizing amount of a combination of an aluminum hydroxide gel as a first fluidizer and a pharmaceutically acceptable citric ion source as a second fluidizer, and a polyhydric alcohol. The composition may also contain other therapeutically active substances such as sucralfate.
U.S. Pat. Nos. 4,670,185 and 4,676,984, issued to Fujiwara et al. and assigned to Lion Corporation, discloses an aqueous vesicle dispersion comprising (1) a nonionic surfactant selected from polyethylene castor oil ethers and polyethylene hydrogenated castor oil ethers, (2) a nonionic surfactant which is a sorbitan polyester, and (3) an ionic surfactant. The dispersions may be used as release-controlled agents and may contain topical agents such as peptic ulcer remedy medicaments which include sucralfate.
U.S. Pat. No. 4,615,697, issued to Robinson and assigned to Bio-Mimetics, Inc., discloses a controlled release composition comprising a bioadhesive comprised of a water-swellable but water-insoluble carboxy-functional polymer and a treating agent which may be sucralfate.
M. Itch et al., Gastroenterology, 96, p. A229 (May 1989), "Combination of EGF and Sucralfate Significantly Accelerates The Healing of Chronic Gastric Ulcers In The Rat," discloses the combination of epidermal growth factor (EGF) and sucralfate for treatment of chronic gastric ulcers. Sucralfate is said to enable EGF to remain in the stomach at a high concentration.
A frequently encountered problem in the field of chewable medicament encapsulated compositions is unsuitable particle size and shape. Particle sizes larger than about 850 microns are usually considered unsatisfactory for chewing because these particles are gritty and are easily broken during chewing thereby causing premature release of the medicament in the mouth with an accompanying off-taste. Spheroidal particles are generally preferred over non-spheroidal particles because these uniformly coated materials protect the medicament from premature release and release the medicament more uniformly.
Small medicament encapsulated particles, or microcapsules, suitable for use in chewing compositions are generally easier to prepare with a solvent-based film coating because of the high volatility and low surface tension of the solvent. For the reasons set out above, microcapsules prepared from aqueous-based coating materials are usually preferred, however, these microcapsules are generally larger in size than those obtained from solvent-based coating materials and must be ground to obtain smaller chewable microcapsules. These ground smaller particles are usually not satisfactory for use in medicament encapsulated compositions because the particles are irregular, are not spheroidal and do not release the medicament uniformly.
U.S. Pat. No. 4,749,575, issued to Rotman and assigned to Bio-Dar Ltd., discloses the preparation of chewable microcapsules of less than 300 microns diameter formed by dissolving a polymer such as hydroxypropyl methylcellulose phthalate, hydroxyphenyl methylcellulose or various acrylic resins in an organic solvent and coating a medicament with the polymer solution in a fluidized bed.
European patent application no. 266,113 discloses a method for preparing a taste masked therapeutic composition which comprises spray drying a suspension of acetoaminophen in a solution of an acrylic polymer in an organic solvent.
European patent application no. 250,648 and Goodman et al., Journal of Pharmaceutical Sciences, 59, 1131-1137 (1970), disclose methods for preparing microspheres suitable for formulating into a tablet which comprise slurrying an aqueous mixture of a drug and an acrylic polymer, vacuum drying the mixture, then grinding the so-formed particles, and compressing the particles into a tablet.
PCT application no. PCT/U.S.87/03068 discloses a method for preparing a taste-masked pharmaceutical composition which comprises spraying in a fluidized bed a suspension comprised of a mixture of an aqueous based solution of a high temperature film forming polymer and a low temperature film forming polymer onto particles of a pharmaceutical core material. The high temperature film forming polymer can be ethyl cellulose or an acrylic polymer and the low temperature film forming polymer can be an acrylic polymer.
European patent application no. 265,226 discloses a method for preparing a taste masked therapeutic composition which comprises spray drying a suspension of colloidal silica in an alcoholic solution of acetoaminophen and ethyl cellulose.
U.S. Pat. No. 4,764,380, issued to Urquhart et al. and assigned to Alza Corporation, discloses a drug delivery system for microcapsules which can be prepared from an aqueous mixture of the drug and ethyl cellulose. The mixture is blended and kneaded, then extruded and passed through a 20 mesh screen. The microcapsules may be coated with ethyl cellulose by air suspension.
While the above medicament encapsulated compositions provide some degree of taste masking activity, none of the above compositions are entirely satisfactory. Chewable encapsulated compositions prepared from organic solvent based polymer solutions are expensive and pose environmental and toxicity problems. Chewable encapsulated compositions prepared from aqueous dispersions of polymers generally provide large microcapsules which must be ground to smaller particles which are usually not uniform in size, shape and composition. Thus it would be advantageous to prepare an encapsulated composition from an aqueous dispersion of polymer whereby the microcapsules formed are spheroidal and are of sufficiently small size such that they are not gritty and can be chewed without being broken. The present invention provides such improved chewable spheroidal microcapsules and taste masking compositions without the disadvantages characteristic of previously known products. The present invention also provides methods for preparing these improved spheroidal microcapsules and taste masking compositions in which they may be employed.